Regional differences in peroxidatic activation of paracetamol (acetaminophen) mediated by cytochrome P450 and prostaglandin endoperoxide synthetase in rabbit kidney.
Microsomes from renal cortex, outer medulla, and inner medulla of rabbit kidneys were found to catalyze the metabolic activation of paracetamol (acetaminophen), leading to covalent binding to protein when incubated with cumene hydroperoxide and T-butyl hydroperoxide. Differential distribution of cytochrome P450 and prostaglandin endoperoxide synthetase and each enzyme's preference for either cumene hydroperoxide or T-butyl hydroperoxide enabled the present investigation to distinguish their respective contributions in the cooxidative activation of paracetamol. Addition of methemoglobin caused enhancement of prostaglandin endoperoxide synthetase mediated activation of paracetamol when initiated by both arachidonic acid and the hydroperoxides. Aspirin and indomethacin inhibited the protein covalent binding of the reactive metabolite of paracetamol only when its formation was initiated by arachidonic acid. This study demonstrates the differences in the peroxidation metabolic activation of paracetamol mediated by cytochrome P450 (cortex greater than outer medulla greater than inner medulla) and prostaglandin endoperoxide synthetase (inner medulla greater than outer medulla greater than cortex) in rabbit kidney.
D000082:Acetaminophen / Q000378:metabolism*; D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000494:pharmacology; D001711:Biotransformation; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism*; D006358:Hot Temperature; D066298:In Vitro Techniques; D007668:Kidney / Q000201:enzymology*; D008297:Male; D008706:Methemoglobin / Q000502:physiology; D009928:Organ Specificity; D010545:Peroxides / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D011489:Protein Denaturation; D011817:Rabbits
D001095:Arachidonic Acids; D010545:Peroxides; D016718:Arachidonic Acid; D000082:Acetaminophen; D008706:Methemoglobin; D003577:Cytochrome P-450 Enzyme System; D011451:Prostaglandin-Endoperoxide Synthases